tbuckley/cabot-search huggingface dataset:
Abstract 3706: The significance of cholesteryl ester profiles in hepatocellular carcinoma
Authors: Nazar Rahmanov, Zhirong Liu, Jinghe Mao, Patrick Kyle, Xinchun Zhou
Journal: Cancer Research (2023)

Abstract Introduction: The association between cholesteryl ester (CE) profiles in the liver and oncogenesis, gender, and age disparities in hepatocellular carcinoma (HCC) has not been studied to date. This study aims to compare CE profiles between benign liver tissue (BLT) and HCC, and to correlate these findings with oncogenesis and disparities in patients with HCC. Methods: Paired BLT and HCC samples obtained from 32 patients with the diagnosis of HCC were used for lipid extraction. Electrospray ionized mass spectrometry (ESI-MS) was used to determine CE profiles, including 22 individual CE species and the total levels of CE. The CE profiles in BLT and HCC were compared and stratified between subgroups based on the gender and age of the patients. The student T-test was used for statistical analysis and the significant p-value was set at 0.05. Results: Total CE levels were higher in HCC than in BLT, but not statistically significant (1.8-fold, p=0.16). Interestingly, 5 saturated CE individual species and 2 mono-unsaturated individual CE species (C14:0, C16:0, C16:1, C18:0, C18:1, C19:0, and C20:0) were significantly higher in HCC than in BLT (2.4 to 14-fold higher). None of the individual poly-unsaturated CE species showed a statistical difference between HCC and BLT. In males, the levels of 3 saturated individual CE species (C16.0, 16:0, and C20:0) were significantly higher in HCC than in BLT (1.9 to 21.3-fold higher levels). In contrast, CE 16:1 was significantly lower in HCC than in BLT (0.9-fold, p=0.02) in males. In females, none of the CE profiles showed a significant difference between HCC and BLT. Total CE levels were 2.1-fold higher in males with HCC than in females with HCC (18.6nM vs. 8.92nM). In young patients (&amp;lt;66-year-old), individual CE species C14:0 was significantly higher in HCC than in BLT (19.1-fold, p=0.038). In old patients (≥66-year old), individual CE species C20:0 was significantly higher in HCC than in BLT. Total CE levels were 2.1-fold higher in young HCC patients than in old HCC patients (13.68nM vs. 6.45nM). Conclusion: This study reveals that an increase in hepatic total CE levels and individual CE species are associated with the oncogenesis of HCC and show gender and age disparities. These findings could be helpful in prevention, treatment, exploring biomarkers, and understanding disparities in HCC. Citation Format: Nazar Rahmanov, Zhirong Liu, Jinghe Mao, Patrick Kyle, Xinchun Zhou. The significance of cholesteryl ester profiles in hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3706.
Abstract 157: Patient in the lab: Down-scaling patient-derived organoid screening for diagnostic purposes
Authors: Esmee Koedoot, Inez van Weersch, Gakuro Harada, Masahiko Watanabe, Hamdy Warda, Hideaki Kyan, Yasmine Abouleila, Takahiko Kumagai, Yuichi Hikichi, René Overmeer, Jeanine Roodhart, Kiyotaka Matsuno, Carla Verissimo, Sylvia F. Boj
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related death. A large fraction of the CRC patients diagnosed with de novo metastatic disease do not benefit from standard of care and experience substantial side effects. Therefore, there is an urgent need for preclinical models that help predict patient response in the clinic. Patient-derived organoids (PDOs or HUB Organoids®) represent a significant breakthrough as preclinical models as they are directly established from patient tissue and faithfully recapitulate patient disease. HUB Organoid Technology can already be applied to preclinical drug screening, however, to provide direct patient benefit the turnaround time between patient diagnosis and PDO-based results must be shortened. In collaboration with Yamaha Motor, the Yamaha CELL HANDLERTM has been validated to automatically pick-and-place with high accuracy a significantly reduced number of organoids per screening plate, compared to standard procedures. In addition, an image-based readout was developed that enables a precise quantification of organoid number ensuring high assay quality. Organoid responses to chemotherapy and targeted agents were validated using this newly automated system, confirming comparable PDO-patient drug sensitivity profiles, and known drug responses based on genetic dependencies. In summary we describe the development of an automated workflow that combines patient-representative HUB Organoids and state-of-the-art robotics by Yamaha CELL HANDLER. This workflow down-scales the number of organoids needed per screening well and allows to efficiently predict patient response, thereby reducing the diagnostic turnaround time and increasing patient benefits. Citation Format: Esmee Koedoot, Inez van Weersch, Gakuro Harada, Masahiko Watanabe, Hamdy Warda, Hideaki Kyan, Yasmine Abouleila, Takahiko Kumagai, Yuichi Hikichi, René Overmeer, Jeanine Roodhart, Kiyotaka Matsuno, Carla Verissimo, Sylvia F. Boj. Patient in the lab: Down-scaling patient-derived organoid screening for diagnostic purposes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 157.
Abstract 2263: Complete remission of a patient with Merkel cell carcinoma treated with durvalumab
Authors: Saad Sabbagh, Barbara Dominguez, Houssein Abdul Sater
Journal: Cancer Research (2023)

Abstract Merkel cell carcinoma (MCC) is a rare, cutaneous, neuroendocrine tumor that is highly aggressive. It is the second leading cause of death from skin cancer, after melanoma, despite accounting for less than 1% of malignant skin tumors. Due to the characteristic histopathological neuroendocrine features of the neoplasm, cases of MCC are often misdiagnosed as undifferentiated skin cancers or other tumors with small blue cell types. Clinical examination fails to establish the diagnosis in 99% of cases and pathological assessment by biopsy with immunohistochemistry is essential to confirm MCC diagnosis. Historically, cytotoxic chemotherapy combinations with platinum-based agents (Carboplatin or Cisplatin) plus Etoposide or Cyclophosphamide, Epirubicin, and Vincristine (CAV) agents were the primary systemic treatment for advanced cases. Despite available evidence sensitivity of MCC to chemotherapy, responses are not durable, and the literature is not supportive of combination chemotherapy (NCCN guidelines). The introduction of immunotherapy such as checkpoint inhibitors (ICI) particularly PD-1/PD-L1 blockers increased overall survival and achieved durable tumor regression in clinical trials leading to FDA approval in locally advanced and metastatic disease. Permbrluzimab and Avelumab are the only two FDA-approved ICIs as first-line standard-of-care treatments for MCC patients. What we are missing is data or trials examining the efficacy of other ICI such as Durvalumab, (anti-PD-L1) in MCC. We hereby report an unprecedented case of an 84-year-old female MCC patient with extensive axillary nodal involvement achieving complete remission after treatment with Durvalumab combined with Carboplatin and Etoposide. Citation Format: Saad Sabbagh, Barbara Dominguez, Houssein Abdul Sater. Complete remission of a patient with Merkel cell carcinoma treated with durvalumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2263.
Abstract 2516: Analysis of CLL Celllular Environment and Response (ACCER) is a novel method to understand the microenvironment in CLL
Authors: Spencer Gibson, Tricia Choquette, Elizabeth S. Henson, Xioyan Yang, James B. Johnston
Journal: Cancer Research (2023)

Abstract Microenvironments such as lymph nodes and bone marrow allow chronic lymphocytic leukemia (CLL) cells to survive after drug treatments. There are limited methods to study the to study the contribution of the microenvironment. We have adapted a solid tumour microenvironment cell culture system that provides elements of the CLL microenvironment called Analysis of CLL Cellular Environment and Response (ACCER). We optimized the cell number for patient’s primary CLL cells and HS-5 human bone marrow stromal cell line that will give sufficient cell number and viability with the ACCER. We then determined the amount of collagen type 1 to give the best extracellular matrix to seed CLL cells to the membrane. Finally, we determined that ACCER provide CLL cell protection against cell death following treatment with fludarabine and ibrutinib compared to co-culture conditions. This describes novel microenvironment model to investigate factors that promote drug resistance and cell survival in CLL. In the future, this will further validate new treatment strategies to overcome microenvironmental CLL cell survival signals. Citation Format: Spencer Gibson, Tricia Choquette, Elizabeth S. Henson, Xioyan Yang, James B. Johnston. Analysis of CLL Celllular Environment and Response (ACCER) is a novel method to understand the microenvironment in CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2516.
Abstract 826: Illuminating cancer cells with a novel nano fluorescent NIR probe for bioimaging
Authors: Neeraj Chauhan, Marco Cabrera, Pallabita Chowdhury, Prashanth K. Nagesh, Anupam Dhasmana, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu
Journal: Cancer Research (2023)

Abstract Background: Adequate bioimaging is crucial in cancer management in many ways including screening, detection, characterization, staging and grading, therapy response, surgical guidance, and margins assessment. Indocyanine green (ICG) is one of the FDA-approved near infra-red fluorescent (NIRF) probe for cancer imaging and image-guided surgery in clinical setting. However, limitations of ICG includes poor photostability, high concentration toxicity, short circulation time, and poor cancer cell specificity. To overcome these hurdles, we engineered a nanoconstruct composed of poly(vinyl pyrrolidone) (PVP)-indocyanine green that is cloaked self-assembled with tannic acid (termed as ICG-Glow NPs) for the cancer cells/tissues specific targeting. Methods: Pursuing the novel nanotherapy approach, our lab has developed PVP-TA based ICG (PVT-ICG) fluorescent nanoparticles via self-assembly process. Our optimized PVT-ICG nanoformulation was further characterized for its physicochemical properties. An IVIS imaging system was further used to measure NIR fluorescence of novel PVT-ICG. Moreover, Human cancer (Breast, Pancreatic, Liver and Prostate) tissue microarrays (TMAs) were histochemically stained to assess cancer cell targeting/specificity of PVT-ICG. Results: PVT-ICG indicated particle size and surface charge ideal for cancer cell/tissue delivery. PVT-ICG, further, demonstrated improved photostability and fluorescent intensity. Additionally, TMA studies exhibited enhanced internalization and cancer targeting/specificity of PVT-ICG nanoparticles compared to free ICG dye in all cancers. Conclusion: Collectively, our findings suggest that this NIR fluorescent probe PVT-ICG has great potential for becoming a novel and safe imaging modality for various types of cancer cells and tumors which can result in early cancer diagnosis leading to improved disease management. Citation Format: Neeraj Chauhan, Marco Cabrera, Pallabita Chowdhury, Prashanth K. Nagesh, Anupam Dhasmana, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu. Illuminating cancer cells with a novel nano fluorescent NIR probe for bioimaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 826.
Abstract 2518: Heterogeneity of cytokine secretion in single senescent fibroblasts is impacted by ONC201 and ABT-263
Authors: Lanlan Zhou, Shengliang Zhang, Kelsey E. Huntington, Benedito A. Carneiro, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote cancer. During the process of aging, cellular and molecular changes that occur in non-cancerous cells can alter responses to cancer therapy and immune response in the tumor microenvironment (TME). Targeting senescent cancer-associated fibroblasts (CAFs) by means of removal, modulation of the SASP, or through cellular reprogramming represent therapeutic avenues for treating cancer. Heterogeneity of CAFs is emerging as an important area of investigation in cancer therapy. To better elucidate the interplay between cancer cells, immune cells, and senescent fibroblasts from different tissues and determine their impact on tumor growth and response to cancer therapy, we investigated the heterogeneity of cytokine secretion in senescent fibroblasts by a single cell cytokine assay. Control and treated proliferating and senescent fibroblasts were loaded onto IsoPlexis IsoCode chips coated with multiplexed antibodies which allows detection of 32 cytokines at a single-cell level for frequency and intensity. The Polyfunctional Strength Index (PSI) showed that stimulatory and chemo-attractant cytokines were dominant in the senescent fibroblasts. The Polyfunctional heat map showed that there are subpopulations of cells which have polyfunctional cytokine secretion (&amp;gt;2 different cytokines) in live senescent IMR90 cells. Treatment with ONC201 reduced cytokine polyfunctionality in live senescent IMR90 cells. Although ABT-263 (small molecule inhibitor of Bcl-2, Bcl-XL) did not show a significant reduction of polyfunctionality in live senescent IMR90, the frequency showed that ABT-263 reduced the secretion frequency of live senescent IMR90 cells except for GM-CSF. Combining ONC201 and ABT-263 diminished polyfunctionality and secretion frequency of senescent IMR90 cells except for MIF which was detected in 1.5% of the cells. Single cell cytokine profiling of live cells in the complex tumor microenvironment is providing insights into tumor progression, therapy resistance, and the effects of senolytic drugs and drug combinations. Citation Format: Lanlan Zhou, Shengliang Zhang, Kelsey E. Huntington, Benedito A. Carneiro, Wafik S. El-Deiry. Heterogeneity of cytokine secretion in single senescent fibroblasts is impacted by ONC201 and ABT-263 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2518.
Abstract 3666: A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle
Authors: Ruizhong Wang, Brijesh Kumar, Poornima Bhat-Nakshatri, Aditi Sanjay Khatpe, Michael P. Murphy, Kristen E. Wanczyk, Emma H. Doud, Amber L. Mosley, Yunlong Liu, Duojiao Chen, Ed Simpson, Hongyu Gao, Harikrishna Nakshatri
Journal: Cancer Research (2023)

Abstract Skeletal muscle dysfunction due to the effects of cancer secretome is observed in multiple cancer types and extreme dysfunction is manifested as cachexia. Major preclinical studies on cancer-associated muscle defects utilized mouse models or mouse C2C12 mouse myoblast cell line for in vitro studies. Because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required to fully comprehend the effects of cancer secretome on skeletal muscle. Here, we report a simple method to establish skeletal muscle stem cell line (hMuSC), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with hMuSCs to myotube transition. Cancer cell line derived factors accelerated stem to myotube differentiation with accompanying changes including an increase in PAX7+/MyoD+ myogenic progenitor cells. Among the pathways activated by cancer-derived factors include inflammatory pathway involving CXCL8 (also called IL-8), glucocorticoid receptor (GR) pathway, and wound healing pathway. Furthermore, cancer-derived factors significantly altered splicing machinery in hMuSCs. Additionally, AKT and p53 pathways that function in metabolic/survival pathways of the skeletal muscle were adversely affected when hMuSCs were exposed to cancer cell-derived factors. Cancer-derived factors increased the expression levels of previously known cachexia-associated genes such as MT-2, ZIP14, and PDK4. Thus, the model system not only recapitulates results of previous mouse studies but also provides much needed human model system that can easily be adapted for large scale studies to explore the epigenomic changes during hMuSC differentiation and to screen for drugs that restore skeletal muscle function in various diseases. Citation Format: Ruizhong Wang, Brijesh Kumar, Poornima Bhat-Nakshatri, Aditi Sanjay Khatpe, Michael P. Murphy, Kristen E. Wanczyk, Emma H. Doud, Amber L. Mosley, Yunlong Liu, Duojiao Chen, Ed Simpson, Hongyu Gao, Harikrishna Nakshatri. A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3666.
Abstract 1416: Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis
Authors: Shigekatsu Maekawa, Masahi Fujita, Ryo Takata, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Jun Sugimura, Takaya Abe, Hidewaki Nakagawa, Wataru Obara
Journal: Cancer Research (2023)

Abstract Introduction: Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study’s goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Materials and Methods: Frozen kidney samples were obtained from 48 patients who were undergoing dialysis treatment and developed RCC at Iwate Medical University Hospital. Among them, we selected 38 subjects for study from whom matched tumor and adjacent non-tumor tissue samples could be obtained and from which DNA (n=38) or RNA (n=26) could be isolated. We performed whole genome sequencing of genomic DNA using MGIEasy FS DNA Library Prep Set and short read sequencer DNBSEQ-G400. mRNA Sample were sequenced using HiSeq. Driver events, copy-number alteration (CNA) analysis, and mutational signature profiling was performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels, and structural variants as well as CNAs, while transcriptome data was analyzed for differentially expressed genes and through gene set enrichment analysis. Results: ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All ACD (acquired cystic disease)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation, and targets of Myc. Conclusion: This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis. Citation Format: Shigekatsu Maekawa, Masahi Fujita, Ryo Takata, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Jun Sugimura, Takaya Abe, Hidewaki Nakagawa, Wataru Obara. Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1416.
Abstract 3659: RAS drivesmalignancy through stem cell crosstalk with the microenvironment
Authors: Shaopeng Yuan
Journal: Cancer Research (2023)

Abstract Squamous cell carcinomas (SCCs) are triggered by marked elevation of RAS/MAPK signaling and progression from benign papilloma to invasive malignancy. At tumor-stromal interfaces, a subset of tumor-initiating progenitors, the cancer stem cells (CSCs), obtain increased resistance to chemo and immunotherapy along this path. The distribution and changes in CSCs during progression from a benign state to invasive SCC remain elusive. Here, we show that following HRASG12V activation, CSCs rewire their gene expression program and trigger a self-propelling, aberrant signaling crosstalk with their tissue microenvironment that drives their malignant progression. Surprisingly, the non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways often mutated in advanced metastatic SCCs with high mutational burden. Coupling our clonal skin HRASG12V model with single-cell transcriptomics, chromatin-landscaping, lentiviral reporters and lineage-tracing, we show that aberrant crosstalk between CSCs and their microenvironment triggers angiogenesis and TGFβ-signaling, creating conditions ripe for hijacking leptin and leptin receptor (LEPR)-signaling, which in turn launches downstream PI3K-AKT-mTOR signaling at the benign-malignant transition. By functionally interrogating each step in this pathway, we unravel how dynamic temporal crosstalk with the microenvironment and orchestrated by the stem cells (SCs) profoundly fuels this path to malignancy. These new insights suggest broad implications for cancer therapeutics. Citation Format: Shaopeng Yuan. RAS drivesmalignancy through stem cell crosstalk with the microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3659.